Jan 19, 2011
The therapeutic development of monoclonal antibodies – the poster child of the biologics revolution – was supposed to herald a new, modern age in which genomic data would identify proteins involved in disease and genetic engineering would produce new molecules against these targets. Much of this scenario has come true: genomics frequently steers research and there has been an explosion of tools to find or create antibodies de novo. But rather than being a cookie-cutter recipe for clinical success, too many of these antibodies fail during development. This is a vexing problem: if molecules are built to atomic specification and designed to bind a validated target with high specificity, why don’t they work as expected? Why do billion dollar pipelines turn into pipe dreams? Why is the probability of disappointment still so high? Adimab, a New Hampshire-based start-up with MIT roots, has a technology it claims can dramatically increase the success rate of monoclonal antibody therapeutics. A growing chorus of major pharmaceutical companies seems to agree.
Monoclonal antibodies are a very attractive therapeutic class. Roche’s antibody portfolio of Avastin, Rituxan and Herceptin – recently acquired in the merger with Genentech – pulled in over $10B in the first half of 2010 alone[i]. Many industry analysts expect broad market growth in the coming decade for both traditional and next-generation antibody therapeutics, such as multi-specific molecules and antibody-drug conjugates.
The rosy projections are due in part to the well-documented success rate of protein therapeutics compared to small molecules. Twenty-three percent of protein drugs that entered clinical development from 1993-2004 were eventually approved for use, compared to just 13% for small molecules[ii]. Additionally, monoclonal antibodies face limited competition from generics. The FDA has yet to announce what hurdles so-called biosimilar molecules will have to clear, but recent safety-first decisions at the agency suggest that the path to approval will not be easy. Since the cost of manufacturing a follow-on biologic molecule can easily surpass $100M and approval is far from guaranteed, the list of competitors may be short[iii].
Life Science Digest points to the frequency with which monoclonal antibody companies are acquired as further evidence of the strength of the class. The last five years have seen at least one significant deal per year with a median value of $700M (Table 1)
A more sober interpretation of the same data is that Big Pharma recognizes the value of having monoclonal antibodies in the pipeline, but has seen the discovery well dry up. Perhaps the M&A activity reflects this failure to develop monoclonal antibodies in house, which has created an across-the-board scramble to buy up the few small companies that have succeeded.
In support of this hypothesis, it is worth noting that these deals often include more than just individual therapeutic candidates. In the antibody space, Big Pharma is seeking access to the geese that lay the golden eggs – the broader platforms and technologies from which to generate new molecules from scratch. Some of these, such as transgenic mice that can make human antibodies or comprehensive libraries of antibodies displayed on bacteriophage, have commanded large sums on the market in recent years (Table 2).
With all this activity, one would think the industry’s problems would have been solved. If new technologies for generating human antibodies make the creation of new molecules trivial, then an effective antibody should be quickly found against every target of interest. But despite the rash of acquisitions, problems remain. Most of these new technologies are relatively unproven. They come recommended by a single clinical success and healthy dose of hype, but have not yet panned out as robust discovery engines.
Phage-displayed libraries, for example, screen only the portion of the antibody responsible for the binding interaction. When the entire antibody is reassembled, it is often prone to aggregation or low yield from cell culture. Animal hybridoma technology is time-intensive and low-throughput, as individual antibody-producing cells need to be isolated, immortalized, and cultured. As a result, it is difficult to generate more than a few antibodies at a time.
Enter Adimab. The New Hampshire-based company founded by Tillman Gerngross of GlycoFi fame and MIT professor K. Dane Wittrup, has stepped into the fray with an innovative platform that promises a better solution. Adimab’s technology is a proprietary library of 100 trillion human antibodies produced in yeast. Partner companies send Adimab a target molecule and Adimab returns a hundreds of full-length, well-behaved, fully human antibodies. The partner can then test these antibodies in cell culture or animal models and move the most promising candidates forward.
Adimab’s system provides some significant advantages over current alternative technologies discussed above:
1. Quality. Since the antibodies are produced as full-length proteins in yeast, the manufacturing quality control is inherent to the platform. Aggregation, for instance, is not observed with Adimab antibodies.
2. Quantity. Adimab creates hundreds of highly specific leads. Typically, the funneling of many molecules to a few leads is done by measuring molecular properties in vitro, such as the affinity of the antibody for its target, or specificity of the antibody to a particular region on the target protein. These properties, however, are rarely predictive of in vivo efficacy. Adimab’s technology provides the partner with a large number of antibodies that all meet in vitro standards. The partner can then select a lead molecule using data from more physiologically-relevant cell culture or animal assays.
3. Speed. The typical turnaround time for Adimab from receipt of the target protein to delivery of antibodies is eight weeks. By outsourcing the discovery process to Adimab, the partner companies can focus on their area of expertise – clinical development – rather than expending energy on protein engineering. Additionally, many cancer antibodies target the same set of tumor-associated proteins. In this competitive environment, time to market is a crucial parameter in the financial success of a therapeutic. Adimab provides the fastest route from target selection to preclinical testing.
The partnerships have been rolling in for Adimab in the past twelve months. Roche, Merck, Pfizer, Novartis, Eli Lilly, Genentech and Human Genome Sciences have all inked deals with Adimab, along with eight more unnamed partners[v]. FierceBiotech recognized the run of good press by naming Adimab a Fierce 15 company for 2010[vi]. Beyond just hype, two early trial participants, Roche and Merck, have already announced that Adimab’s antibodies met or exceeded the original expectations. The company expects more good reviews in the near future.
Dane Wittrup, Adimab’s Chief Scientific Officer, points out that these deals are of the “test drive” variety. Adimab is actively pursuing a variety of deal structures to transfer their technology to Big Pharma partners. Following such technology transfers, Adimab may begin to pursue in-house discovery and other creative partnerships, but for now the company is focused on building and proving the merit of its technology.
One hurdle Adimab faces in the adoption of its technology is that it produces its antibodies in yeast, an organism that glycosylates proteins – coats them with sugar molecules – differently than mammalian cells do, which can have profound biological and therapeutic consequences. Adimab’s acquisition history (Genetastix in 2007)[vii] and founder pedigree (GlycoFi’s raison d’être was to mimic human sugar patterns in yeast) suggest that the company has found a way to control glycosylation, but changing the behavior of the biotech industry is another matter. Mammalian cell culture has long been the workhorse of industrial protein production and there may be a psychological barrier to switching to yeast for antibody production.
Adimab competitors, such as AnaptsysBio (La Jolla, CA) and Vaccinex (Rochester, NY), have similar antibody library technologies but produce their protein in mammalian cells. AnaptsysBio has established partnerships with Merck and Roche. Adimab holds a speed advantage because yeast grow faster than mammalian cells, but potential clients with experience in mammalian cell culture may prefer to sacrifice a few months of discovery time in exchange for peace of mind and lower development risk.
Adimab has a head start over its competitors, evidenced by the growing list of satisfied test partners, and the company’s savvy business model can turn that advantage into revenue. The field of antibody discovery is crowded with competing intellectual property claims and proprietary technologies, but Adimab makes its platform available to all interested buyers. This open-source approach allows the company to generate profit from multiple partnerships. So long as Adimab’s technology is better than what the industry holds in its arsenal, there will be plenty of suitors. And so long as antibodies remain a lucrative therapeutic class, few will be able to resist seeking access to the same fast-track discovery used by their competitors.
The final verdict on Adimab’s technology must wait until molecules from the platform reach the clinic, which will take several years, but at the moment the company looks like a can’t-miss entrepreneurial hit. If it can simultaneously speed the discovery process and up the odds of clinical success, Adimab may even rescue the monoclonal antibody.
Disclosure: the author is a graduate student in Dane Wittrup’s lab at MIT.
[ii] DiMasi, et al. Clin Pharmacol Ther. 2010, 87.
[iv] “Monoclonal antibody companies command premiums,” Life Science Digest, July 11, 2010.
[v] Information on deals available at http://www.adimab.com/adimab-partners/ and at http://www.xconomy.com/boston/2010/12/15/adimab-adds-genentech-lilly-and-human-genome-sciences-to-growing-list-of-partners/